Method of producing anorexia

ABSTRACT

A method of producing anorexia in warm-blooded animals which comprises administering a substituted phenoxymethylmorpholine.

United States Patent 1191 Jagger's et al. a

METHOD OF PRODUCING ANOREXIA Inventors: Stuart Edward Jagger's; Juan Luis Madinaveitta; Roy Frederick Maisey, all of Macclesfield, England Assignee: Imperial Chemical Industries Limited, London, England Filed: July 11, 1972 Appl. No.: 270,687

Foreign Application Priority Data Aug. 9, 1971 Great Britain 37299/71 US. Cl. 424/248 Int. Cl A61k 27/00 Field of Search 424/248; 260/247.7 C, 999; 42l/DIG. 11

[ Apr. 23, 1974 Primary Examiner-Albert T. Meyers Assistant Examiner-Norman A. Drezin Attorney, Agent, or Firm-Cushman, Darby & Cushman [57] ABSTRACT A method of producing anorexia in warm-blooded animals which comprises administering a substituted phenoxymethylmorpholine.

5 Claims, No Drawings METHOD OF PRODUCING ANOREXIA This invention relates to anorexiants and in particular it relates to a method of producing anorexia in man and animals.

In this specification the term anorexia is used to mean partial or complete loss of appetite, and this can have the beneficial effect of reducing weight, particularly in obese subjects.

It is well known that sympathomimetic amines such as amphetamine and phenmetrazine produce an anorexiant effect which, on continued administration of a given daily dose, becomes smaller with time. It is also known (UK. Patent No. 1,138,405; US. Patent application Ser. No. 685,302) that phenoxymethylmorpholines have a depressant action on the central nervous system. The basis of the present invention is the discovery that these phenoxymethylmorpholines, which are chemically unrelated to the amphetamines, possess anorexiant activity and further that the effect produced on continued administration of a given dose of the compound is maintained for a longer period than would be the case with amphetamine.

According to the present invention there is provided a method of producing anorexia in warm blooded animals which comprises administering to the man or animal an anorectically effective amount of 2-(oethoxyphenoxymethyl)morpholine or 2-(mmethoxyphenoxymethyl)morpholine or a non-toxic, pharmaceutically-acceptable acid-addition salt thereof.

These compounds have the formula:

methoxyphenoxymethyl)morpholine are effective in producing anorexia, but whereas the (S) isomers produce an anorexiant effect at a dose comparable to that of the racemate, the (R) isomer is less active than the (S) isomer. The invention thus includes the use of a racemate, an (S) isomer or an (R) isomer.

The method of producing anorexia is particularly effective when applied to man, but it is also useful when applied to dogs, particularly obese dogs.

The compounds of the invention may be administered to the man or animal orally or parenterally, for example by intraperitoneal or intramuscular injection. The preferred administration regimen for man is a total dose of 50-300 mg. per day (given in l-3 doses per day) for 2-12 weeks and a particularly preferred regimen is a total daily oral dose of 120-180 mg. given in 3 doses per day for 2-12 weeks.

The preferred administration regimen for dogs is a total dose of 5-200 mg. per day (given in l-3 doses per day) for 2-12 weeks and a particularly preferred regimen is a single daily oral dose of 10 mg./kg. for 2-12 weeks.

The invention is illustratedfbut not limited, by the following Examples:

EXAMPLE 1 Ten femalebeagle dogs which had been maintained on a fattening diet for some months were individually housed and given a normaldiet for 3 weeks in order to o stabilise their weights and food intakes. Four dogs were used as controls, and the' remaining six dogs were orally dosed with 10 mgJkg. of 2-(o-ethoxyphenoxymethyl)- morpholine once a day at 14.00 hours for a period of 6 weeks. Two meals a day were offered to all dogs at I g'ggg 09.00 and 16.00 hours. The six treated and four control 2 dogs were grouped so as to have approximately the same mean group weight and distribution about the g mean.

Individual changes in the body weights of the dogs 40 after six weeks treatmentare given in Table 1, and the in which X is o-ethoxyphenyl or m-methoxyphenyl, and average changes in body measurements are given in it will be observed that they posses an asymmetric car- Table 2.

w TABLE 1 Initial Final Change Weight Weight lbs. as I:

1 45.4 50.7 +5.3 +11.7 Control 2 39.8 41.6 +1.8 4.5 Mean change Doll 3 35.0 37.6 +2.6 7.4 +2.85 1 1.8011",

1 44.11 37.9 -6.9 -|s.4 2 43.0 36.6 -6.4 -1s.0 Treated 3 38.0 38.5 +0.5 1.0 Mean change 06 1 4 32.1 31.6 -0.5 1.6 -2.60 t 3.0 163.

bon atom. marked 2 in the above formula and the ra- TABLE 2 cemic form of each may therefore be resolved into two I optically active forms by conventional means. These Measurement Group Before drug Aflfldflll optically active forms may be defined In terms of their Lew, ommh 361 36.2 absolute configuration at the asymmetric carbon atom (cm) TM! 2. using the (R) and (S) system of nomenclature (for COMM (cm!) Treated 24.8 22.8 an explanation of this system see R. S. Cahn, C. K. In- 5 hwy Comm], 23g 2) (ems) Treated 23.7 20.5

gold and V. Prelog, Angew, Chem. Intern. Ed., 1966, 5, 385). Both the (R) and (S) isomers of 2-(0- ethoxyphenoxymethyl)morpholine and 2-(m- The food intake of the dogs for a period of nine weeks was also recorded, and .the results are given in These results are considered to be preliminary only because of the limited number of experiments. However it is clear that the (S) isomer has a similar potency to the racemate (Ex. 2) and the (R) isomer is active al- 5 though less potent.

Table 3. Dosing commenced at the beginning of week 1 and stopped at the end of week 6. Before dosing commenced, the mean food intake per day of the control dogs was 1235 g. and of the treated dogs was 1114 g. During dosing, depression of food intake was seen in the treated dogs whereas the control dogs tended to show an increased food intake. Three weeks after dos- A male Volunteer g height 180 Weight 76 ing ceased, the treated dogs food intake had increased kg. was dosed orally with 80 mg. of 2-(oto the point at which it was not significantly different 10 ethoxyphenoxymethyl)morpholine at 08.00 hours. He from that of the control dogs. did not normally eat breakfast and none was eaten that TABLE 3 Week No. l 2 3 4 5 6 7 8 9 Average food intake for the week gmJdOg/day 1114 1004 713 825 808 934 924 1159 1422 1487 Treated Dogs Change from initial weight eaten 0 10 36 26 27 l6 -l7 4 +28 +34 Average food intake for the week gmJdog/day 1235 1446 1469 1496 1533 1546 1607 1529 1498 1435 Control Dogs Change from initial weight eaten 0 +17 +19 +21 +24 +25 +30 +24 EXAMPLE 2 day. At 10.30 hours the subject was not hungry though he normally was hungry at that time and ate cookies. The subject was dosed with a further-80 mg. of compound at 12.00 hours. At 13.00 hours the subject was not hungry and drank only a cup of coffee. This was very unusual since'on no occasion during the previous year had he not eaten a substantial lunch. At 16.00 hours the subject was closed with a third 80mg. of compound. At 18.30 hours he was presented with a meal which he could not eat, despite having taken no food throughout the day. The subject had felt perfectly well throughout the day and the only effect that he could Mice weighing about 20 g. were starved for 48 hours, divided into groups of 10 (treated) and 20 (controls) and dosed orally with 0.2 ml. of vehicle with or without the drug. Food in the form of a length of uncooked spaghetti was offered immediately after dosing and the length of spaghetti eaten was measured after 1 hour. (The control mice ate continuously since they were hungry and the spaghetti was hard). The results are given in the Table in which the length of spaghetti eaten per mouse by the 10 treated mice is expressed as a percentage of that eaten by the 20 control mice.

.W TABLE Dose in mg./kg. 30 10 3 l of control 39 63 86 89 2-(o-ethoxynumber of phenoxymcthyl)- experiments 8 9 8 6 morpholinc standard error 8.5 5.0 7.7 6.2

- of control 9 71 79 Z-(m-methoxynumber of phenoxymcthyl)- experiments 5 8 8 6 morpholinc standard error 8.8 7.6 6.7 5.9

EXAMPLE 3 detect was a'loss of appetite. It was not known to him 5 that anorexia was a possible effect of an oral dose of 2- (o-ethoxyphenoxymethyl)morpholine and he had previously taken part in studies which involved swallowing tablets of other substances without experiencing a loss of appetite.

The experiment described in Example 2 was re- 5 peated, except that the treated mice were dosed with the (R) and (S) isomers of 2-(o-ethoxyphenoxymethyl)morpholine. The results are given in the Table.

EXAMPLE 5 A male volunteer, age 33, height 173 cm., weight 66.5 kg., was dosed orally with 100 mg. of 2-(0- TABI..E

Dose in rngJkg. 30 10 3 ethoxyphenoxymethyl)morpholine 2 hours before a (R) 27 89 midday meal. A pronounced anorectic effect was expe- $2135.13? 2 4 2 1 rienced 2 hours after dosing. (S) isomer 'rlzlt'bslogt rol 17 54 88 103 EXAMPLE 6 experiments 2 4 2 l A male volunteer, age 28, height 173 cm., weight 73 kg. was dosed orally with 100 mg. of 2-(oethoxyphenoxymethyl)morpholine 1.5 hours before a meal. A prounounced anorectic effect was experienced which lasted for 2.5 3 hours. The experiment was repeated twice with similar results.

EXAMPLE 7 A male volunteer, age 21, height 170 cm., weight 62 kg. was dosed orally with 80 mg. of 2-(0- ethoxyphenoxymethyl)morpholine at 09.00 hours. A

. x-o-orrT J N H wherein X is selected from the group consisting of oethoxyphenyl and m-methoxyphenyl, and the nontoxic, pharmaceutically-acceptable acid-addition salt thereof.

2. A method as claimed in claim 1 in which the warmbloode'd animal is a man.

3. A method as claimed in claim 1 in which the warmblooded animal is a dog.

4. A method as claimed in claim 2 in which a man is dosed with between 50 and 300 mg. per day of the compound for a period of from 2 to 12 weeks.

5. A method as claimed in claim 3 in which a dog is dosed with between 5 and 200 mg. per day of the com pound for a period of from 2 to 12 weeks. 

2. A method as claimed in claim 1 in which the warm-blooded animal is a man.
 3. A method as claimed in claim 1 in which the warm-blooded animal is a dog.
 4. A method as claimed in claim 2 in which a man is dosed with between 50 and 300 mg. per day of the compound for a period of from 2 to 12 weeks.
 5. A method as claimed in claim 3 in which a dog is dosed with between 5 and 200 mg. per day of the compound for a period of from 2 to 12 weeks. 